The present invention relates to new products having anti-inflammatory, analgesic and antithrombotic activity.
Specifically it relates to cyclo-oxygenase (COX) inhibitors.
It is known that the anti-inflammatory and antithrombotic efficacy of NSAIDs (Non steroid antiinflammatory drugs), also known as FANS (non steroid antiinflammatory drugs), but esoecially their tolerability, seem to be considerably affected by their inhibitory activity of the cyclo-oxygenase (COX) both in the inflammatory site and in the healthy tissue. See for example FASEB Journal 1, 89, 1987; Bioch. Biophys. Acta 1083, 1, 1991. The drawback of these products is that they are toxic, as already described in U.S. Pat. No. 5,861,426.
Nitroderivative compounds, described in said patent, are also known, have an high efficacy in the cyclooxygenase inhibition and a low toxicity. However these compounds show some drawbacks connected to the chemical-physical and structural characteristics of the molecules themselves, these latter being highly lipophilic and therefore having a poor solubility in water. It is well known that the solubilization process is decisive for absorption and interaction with the effector. The poor solubility generally involves a variable and unpredictable efficacy whereby it is difficult to set a correct posology. In practice it is necessary to administer higher doses in order to contain the above mentioned variabilities. The drawback is the risks of a higher incidence of side effects. Another disadvantage bound to the poor solubility of the nitroderivatives of said patent application is that they are difficult to be formulated. It is well known that the solubility in water of a molecule is one of the most important properties affecting the pharmacokinetic and pharmacodynamic processes. For example for parenteral administration, particularly by intravenous route, drugs must be formulated in solutions. In order to increase solubility, when it is unsatisfactory for these uses, the choice of suitable solvents and/or excipients is therefore critical, for example, among the latter, surfactants, etc., can be mentioned. This can lead to drawbacks from the toxicological point of view connected to the excipient tolerability; besides there are other drawbacks for example in the intravenous formulation which, as well known, must not cause haemolysis or incompatibility with blood constituents. Besides it is necessary to notice that it is well known that surfactants and apolar solvents can be irritant. See for example J. Pharm. Science 72, 1014, 1983.
Experiments carried out by the Applicant, wherein 0.1% Tween 80 and 1% dimethylsulphoxide have been used to suspend the nitroxy derivatives of the antiinflammatory compounds described in the patent application WO 95/30641 have shown that these substances were irritant towards the gastric mucous membrane.
It has unexpectedly been found that the derivatives of the present invention, differently from the above mentioned compounds of the prior art, can be solubilized without using the substances commonly used in the pharmaceutical technique to obtain solutions or suspensions, maintaining or even improving the activity of the prior art nitroxy derivatives. A further advantage of the compounds of the present invention is that it is possible to avoid adding to the formulation the excipients, such as for example those above mentioned, which cause or can induce irritant effects.
The antiinflammatory products described in the present application have an high cyclo-oxygenase inhibiting activity combined with low toxicity and pharmacokinetic good responses, and have furthermore a better systemic absorption degree.
This is quite surprising and unexpected since the factors affecting the FANS antiinflammatory and antithrombotic efficacy depend on various parameters whereby it is not possible to foresee a priori the pharmacokinetics, for example the absorbed product fraction, the pharmacodynamic activity, the toxicity and the COX inhibiting properties and most of all, no assumptions can be made to predict or limit the response variability.
An object of the present invention are compounds or organic or inorganic salts of compounds of general formula:
Axe2x80x94X1xe2x80x94N(O)z
for use as medicaments, specifically as antiinflammatory and antithrombotic agents, wherein:
z is an integer and is 1 or 2, preferably 2;
A=R(COXu)t and wherein t is an integer 0 or 1; u is 0 or 1;
X=O, NH, NR1c wherein R1c is a linear or branched C1-C10 alkyl; 
xe2x80x83wherein:
nIX is an integer between 0 and 3, preferably 1;
nIIX is an integer between 1 and 3, preferably 1;
RTIX, RTIXxe2x80x2, RTIIX, RTIIXxe2x80x2, equal to or different from each other, are H or linear or branched C1-C4 alkyl; preferably RTIX, RTIXxe2x80x2, RTIIX, RTIIXxe2x80x2 are H;
Y is a ring containing at least one salifiable nitrogen atom;
preferably Y is an heterocyclic ring, saturated or unsaturated or aromatic, having preferably 5 or 6 atoms and containing at least one or two nitrogen atoms, preferably one or two nitrogen atoms;
R is selected from the following groups:
Group I) wherein t=1 and u=1
xe2x80x83wherein:
R1 is the OCOR, group; wherein R3 is methyl, ethyl or linear or branched C3-C5 alkyl, or the residue of a heterocycle with a single ring having 5 or 6 atoms which may be aromatic, partially or totally hydrogenated, containing one or more hetero-atoms independently selected from O, N and S;
R2 is hydrogen, hydroxy, halogen, a linear or when possible branched C1-C4 alkyl, a linear or when possible branched C1-C4 alkoxyl; a linear or when possible branched C1-C4 perfluoroalkyl, for example trifluoromethyl; nitro, amino, mono- or di- (C1-4) alkylamino;
nI is an integer 0 or 1;
Preferably in the Compounds of Formula Ia) X is Equal to O or NH, R1 is acetoxy, preferably in ortho position with respect to xe2x80x94COxe2x80x94, R2 is hydrogen; in X1RTIX=RTIXxe2x80x2=RTIIX=RTIIXxe2x80x2 H, nIX=nIIX=1 and Y is an aromatic ring having 6 atoms, containing one nitrogen atom, said aromatic ring having the two free valences in position 2 and 6.
Preferably in the Compounds of Formula Ib) R3=CH3, nI=0, X is equal to O, X1 is as above defined for Ia); in this case Ib) is the residue of the acetylsalicylsalicylic acid.
The compounds Ic) of formula Ic1) are the 5-amino salicylic acid derivatives (5-amino-2-hydroxybenzoic acid), for example mesalamine, when the valence is saturated with xe2x80x94COOH.
In the compounds of formula Ic2) at least one of the two carboxyl groups is reacted for obtaining the invention compounds. When both carboxyl groups react, bifunctional compounds are obtained. When the two valences are saturated with xe2x80x94COOH, the compound known as olsalazine is obtained. When one of the two valences instead of xe2x80x94COOH is saturated with xe2x80x94CONHCH2xe2x80x94CH2xe2x80x94COOH, the compound is known as balsalazide, wherein xe2x80x94OH which is in ortho position in the same aromatic ring is substituted with H.
The compounds of formula IC3) are known as sulphalazine: 2-hydroxy-5-[(2-pyridinylamino)sulphonyl]phenyl]azo] benzoic acid when the free valence is saturated with xe2x80x94COOH.
The preferred Ic) compounds have X=O and u=1;
Group II) wherein t=1, u=1
xe2x80x83wherein:
RII5 is H, a linear or branched when possible C1-C3 alkyl;
RII6 has the same meaning as RII5, or when RII5 is H it may be benzyl;
RII1, RII2 and RII3 can independently be hydrogen, a linear or when possible branched C1-C6 alkyl or a linear or when possible branched C1-C6 alkoxy, or Cl, F, Br;
RII4 is RII1 or bromine;
the compounds wherein RII1, RII4 are hydrogen and RII2 and RII3 are chlorine in ortho position with respect to NH are preferred;
RII5 and RII6 are H, X is equal to O, and X1 is as above defined for the compounds of formula Ia);
IIb) is the residue of the 2-[(2-methyl-3-(trifluoromethyl)phenyl]amino]-3-pyridincarboxylic] acid and when the xe2x80x94COOH group is present the compound is known as flunixin;
Group III) wherein t=1, u=1 and R is 
xe2x80x83wherein:
R2a and R3a are H, a linear or when possible branched, C1-C12 alkyl or allyl, with the proviso that when one of the two is allyl, the other is H;
preferably R2a is H, C1-C4 alkyl, R3a is H;
R1a is selected from 
IIID) R1a corresponds to the following formulas: 
xe2x80x83wherein the meanings are the following:
when R1a is as defined in formula (IV), Ketoprofen residue:
RIII1 is H,
RIII2 is H, hydroxy;
preferred are the compounds wherein RIII1 and RIII2 are H,
R3a is H, and R2a is methyl, X=O;
when R1a is as defined in formula (XXI), carprofen residue:
Rxxio is H, a linear or when possible branched alkyl having from 1 to 6 C atoms, a C1-C6 alkoxycarbonyl bound to a C1-C6 alkyl, C1-C6 carboxyalkyl, C1-C6 alkanoyl, optionally substituted with halogens, benzyl or halobenzyl, benzoyl or halobenzoyl;
Rxxi is H, halogen, hydroxy, CN, C1-C6 alkyl optionally containing OH groups, C1-C6 alkoxy, acetyl, benzyloxy, SRxxi2 wherein Rxxi2 is C1-C6 alkyl; C1-C3 perfluoroalkyl; C1-C6 carboxyalkyl optionally containing OH groups, NO2, amino; sulphamoyl, di-alkyl sulphamoyl with C1-C6 alkyl, or difluoroalkylsulphonyl with C1-C3 alkyl;
Rxxi1 is halogen, CN, C1-C6 alkyl containing one or more OH groups, C1-C6 alkoxy, acetyl, acetamido, benzyloxy, SRIII3 being RIII3 as above defined, C1-C3, perfluoroalkyl, hydroxy, C1-C6 carboxyalkyl, NO2, amino, mono- or di-alkyl-amino C1-C6; sulphamoyl, di-alkyl sulphamoyl C1-C6, or di-fluoroalkyklsulphamoyl as above defined; or Rxxi together with Rxxi1 is a C1-C6 alkylene dioxy;
preferred are the compounds wherein Rxxio is H, the linking bridge is in position 2, Rxxi is H, Rxxi1 is chlorine and is in para position with respect to nitrogen;
R3a is H, R2a is methyl and X is O;
when R1a is as defined in the formula (XXXV), residue of the tiaprofenic acid:
Ar is phenyl, hydroxyphenyl optionally mono- or poly-substituted with halogen, alkanoyl and C1-C6 alkoxy, C1-C6 trialkyl, preferably C1-C3, cyclopentyl, cyclohexyl cycloheptyl, thienyl, furyl optionally containing OH, pyridyl;
the preferred compounds of (XXXV) are those wherein Ar is phenyl, R3a is H, R2a is methyl and X is O;
when R1a is as defined in formula (II), suprofen residue, of which the preferred one has been shown, wherein R3a is H, R2a is methyl and X=O, as described and obtained in U.S. Pat. No. 4,035,376 herein incorporated by reference;
when R1a is as defined in formula (VI), R is the residue of indoprofen when R2a=H and R3a=CH3;
of indobufen when R2a is equal to H and R3a=C2H5; X=O, as described and obtained according to U.S. Pat. No. 3,997,669 herein incorporated by reference;
when R1a is as defined in formula (VIII), R is the residue of etodolac when R2a=R3a=H and X=O, as described in and obtained according to U.S. Pat. No. 3,843,681 herein incorporated by reference;
when R1a is as defined in formula (VII), R is the residue of fenoprofen when R3a=H, R2a=CH3 and X=O, as described in and obtained according to U.S. Pat. No. 3,600,437 herein incorporated by reference;
when R1a is as defined in formula (III), R is the residue of fenbufen when R2a=R3a=H and X=O, as described in and obtained according to U.S. Pat. No. 3,784,701 herein incorporated by reference;
when R1a is as defined in formula (IX), R is the residue of flurbiprofen when R3a=H, R2a=CH3, X=O;
when R1a is as defined in formula (X) R is the residue of tolmetin when R2a=R3a=H, X=O, as described in and obtained according to FR 1,574,570 herein incorporated by reference.
In the group IIID) R1a corresponds to the following formulas:
IIIa), when R2a=H and R3a=CH3 the residue of pranoprofen is obtained: xcex1-methyl-5H-[1]benzopyrano-[2,3-b]pyridin-7-acetic acid; in the preferred compound R2a=H, R3a=CH3, u=1 and X=O:
(XXX), when R2a=H and R3a=CH3 the bermoprofen residue is obtained: dibenz[b,f]oxepin-2-acetic acid; in the preferred compound R2a=H, R3a=CH3, u=1 and X=O.
(XXXI), when R2a=H and R3a=CH3, R is the radical of the compound CS-670: 2-[4-(2-oxo-1-cyclohexylidene methyl) phenyl]propionic acid; the preferred compound has R2a=H, R3a=CH3, u=1 and X=O;
(XXXII), when R2a=R3a=H the Pemedolac residue is obtained; the preferred compound has R2a=R3a=H, u=1 and X=O;
(XXXIII), when R2a=R3a=H the pirazolac residue is obtained: derivatives of the 4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolic acid; the preferred compounds have R2a=R3a=H, u=1 and X=O.
(XXXVI), when R2a=H, R3a=CH3, the zaltoprofen residue is obtained; when the residue is saturated with an hydroxyl or aminic group, or with the carboxylic function the compounds are known as dibenzothiepin derivatives; in the preferred compounds R2a=H, R3a=CH, u=1 and X=O.
(XXXVII), when R2a=R3a=H the mofezolac residue is obtained: 3,4-di(p-methoxyphenyl)isoxazol-5-acetic acid when the residue is CH2xe2x80x94COOH; in the preferred compounds R2a=R3a=H, t=1 and X=O;
(XII), when R2a=R3a=H the bromfenac residue is obtained: 2-amino-3-(4-bromobenzoyl)benzeneacetic acid; the preferred compounds have u=1, t=1, X=O, R2a=R3a=H; or t=0;
In the group IV) wherein t=1, u=1, R is 
xe2x80x83wherein:
RIVd and RIVd1 are at least one H and the other a linear or branched when possible alkyl from C1 to C6, preferably C1 and C2, or difluoroalkyl with the alkyl having from 1 to 6 C atoms, C1 is preferred, or RIVd and RIVd1 form together a methylene group;
RIV has the following meaning: 
xe2x80x83wherein the compounds of group IV) have the following meanings: in formula (IIB)
Riv-ii is C1-C6 alkyl, C3-C7 cycloalkyl, C1-C7 alkoxymethyl, C1-C3 trifluoroalkyl, vinyl, ethynyl, halogen, C1-C6 alkoxy, difluoroalkoxy, with the C1-C7 alkyl, C1-C7 alkoxymethyloxy, alkylthiomethyloxy with the C1-C7 alkyl, alkyl methylthio with the C1-C7 alkyl, cyano, difluoromethylthio, phenyl- or phenylalkyl substituted with the C1-C8 alkyl; preferably Riv-ii is CH3Oxe2x80x94, RIVd is H and RIVd1 is CH3, and is known as naproxen residue;
X=O and X1 is as above defined for Ia);
in formula (X B), of which the loxoprofen residue has been shown, described in U.S. Pat. No. 4,161,538 the compounds are preferred wherein RIVd is H and RIVd1 is CH3, X=O and X1 is as above defined for Ia);
in formula (IIIB):
Riv-iii is a C2-C5 alkyl, optionally branched when possiblle, C2 and C3 alkyloxy, allyloxy, phenoxy, phenylthio, cycloalkyl from 5 to 7 C atoms, optionally substituted in position 1 with a C1-C2 alkyl;
the compound in which Riv-iii is 
xe2x80x83and RIVd=H, RIVd1 is CH3, is preferred, a compound known as ibuprofen residue; X=O and X1 is as above defined for Ia);
Group V) 
Group VE) 
In group V), the compounds have the following meanings:
when R is the formula (IIC),
Rvii is H or a linear or branched when possible C1-C4 alkyl;
Rvii-1 is Rvii, or a linear or branched when possible C1-C4 alkoxy; Cl, F, Br; the position of Rvii-1 being ortho, or meta, or para;
the residue of the known Ketorolac is preferred, wherein Rvii and Rvii-1 are H, and A=R (A being the group of the formula Axe2x80x94X1xe2x80x94NO2) and t=0;
when R is the formula (V),
of which the residue of the known tenidap has been mentioned, as described and obtained in U.S. Pat. No. 4,556,672 herein incorporated by reference;
in these compounds of formula (V) A=R and t=0,
when R is the formula (VIIC),
of which the residue of the known tenoxicam has been mentioned, A is RCO, t=1 u=0 or A is R and t=0, as described and obtained in DE 2,537,070 herein incorporated by reference;
when R is the formula (IXC),
wherein A=R and t=0, or A=RCO with t=1 and u=0, the residue of the known piroxicam has been indicated, as described and obtained in U.S. Pat. No. 3,591,584 herein incorporated by reference;
when R is the formula (IIIC)
wherein A=RCOO, t=1 and u=0 or 1; or t=0 and A=R, of which the residue of the known nabumetone has been indicated, as described and obtained in U.S. Pat. No. 4,061,779 herein incorporated by reference;
when R is the formula (IVC)
wherein A=RCOO, t=1 and u=1, of which the indomethacin residue has been indicated, as described and obtained in U.S. Pat. No. 3,161,654 herein incorporated by reference;
when R is the formula (XC), the residue X is known as meloxicam;
the preferred compounds are those wherein A=RCO, t=1 and u=0;
when R is the formula (XI) the residue is known as ampiroxicam
when the end group is xe2x80x94CH(CH3)OCOC2H5; the preferred compounds have A=RCO, t=1 and u=0;
when R is the formula (XIII) and the valence is saturated with H
the residue derives from lornoxicam; the preferred compounds have A=RCO, t=1 and u=0;
when R is the formula (XXXX) and the valence is saturated with H
the compound known as paracetamol is obtained, as described and obtained in U.S. Pat. No. 2,998,450 herein incorporated by reference;
when R is the formula (XXXXI) and the valence is saturated with H
the compound known as Tramadol is obtained, as described and obtained in U.S. Pat. No. 3,652,589; the preferred compounds according to the present invention obtainable with the radicals corresponding to the formulas (XXXX) and (XXXXI) have A=RCO, t=1 and u=0.
Y in the above mentioned X1 formula contains one or two nitrogen atoms in the ring, and preferably selected from the following: 
The preferred of Y is Y12 (pyridyl) substituted in position 2 and 6. The bonds can be also in non symmetric position, for example Y12 (pyridyl) can be substituted also in position 2 and 3; Y1 (pyrazol) may be 3,5-disubstituted.
The X1 precursors, wherein the oxygen free valence is saturated with H and the free valence of the end carbon is saturated either with a carboxylic or hydroxyl group, are commercially available products or are obtainable with methods known in the prior art.
The compounds containing R of group I) of the type Ia) are described in the patent WO 92/01668 wherein the preparation methods are also described. This patent is herein incorporated by reference. The type Ib) compounds are for example prepared by using the method shown in The Merck Index, XI ed., 1989, pag. 16, No. 95 for the residue of the acetylsalicylsalicylic acid. The changes of the compounds of formula Ib) may be obtained by applying the processes mentioned in the patent WO 92/01668.
Compounds Ic) of the Ic1) class, in which the radical is a 5-amino salicylic acid derivative (5-amino-2-hydroxybenzoic acid) known as mesalamine, when the starting radical contains xe2x80x94COOH, are prepared by reduction of the m-nitrobenzoic acid with Zn powder and HCl (see H. Weil et al., Ber. 55B, 2664 (1922)), or by electrolytic reduction: Le Guyader, Peltier, Compt. Rend. 253, 2544 (1961). These publications are herein incorporated by reference.
The starting radical Ic2), when it contains xe2x80x94COOH, is known as olsalazine: 3,3xe2x80x2-azabis(6-hydroxybenzoic) acid; and it is prepared according to EP 36,636 or U.S. Pat. No. 4,528,367, both herein incorporated by reference.
The Ic3) compounds are prepared according to U.S. Pat. No. 2,396,145 herein incorporated by reference.
Equivalent compounds to Ic1), Ic2) and Ic3) contain the substituents mentioned in the above references.
The compounds wherein R is of the group II) are described in the patents WO 94/04484 and U.S. Pat. No. 3,558,690 wherein the preparation methods are also described. These patents are herein incorporated by reference.
The starting compound of IIb), when the valence is saturated with xe2x80x94COOH (flunixin), is obtained according to U.S. Pat. No. 3,337,570 and U.S. Pat. No. 3,689,653, both herein incorporated by reference. The compounds containing the substituents mentioned in the previous patents are equivalent to flunixin.
The compounds wherein R is of group III) are described and obtained with the processes mentioned in the following patents:
patent application PCT/EP/93 03193; for the compounds of formula (IV) see also U.S. Pat. No. 3,641,127; for the compounds of formula (XXI) see also U.S. Pat. No. 3,896,145; for the compounds of formula (IX) residue of flurbiprofen see also U.S. Pat. No. 3,755,427; for the compounds of formula (II) see also U.S. Pat. No. 4,035,376; for the compounds of formula (VI) see also U.S. Pat. No. 3,997,669; for the compounds of formula (VIII) see also U.S. Pat. No. 3,843,681; for the compounds of formula (VII) see also U.S. Pat. No. 3,600,437; for the compounds of formula (III) see also U.S. Pat. No. 3,784,701.
All the Above Mentioned Patents are Herein Incorporated by Reference.
The processes for preparing the compounds of class IIID) are the following:
The residue IIIa) is obtained by preparing the acid compound according to U.S. Pat. No. 3,931,205, the valence is saturated with xe2x80x94CH(CH3)xe2x80x94COOH. The compounds containing the substituents mentioned in the above patent are equivalent to pranoprofen. The residue (XXX) is prepared through the compound with the xe2x80x94CH(CH3)xe2x80x94COOH group (bermoprofen) according to U.S. Pat. No. 4,238,620 herein incorporated by reference. Other equivalent products are described in the above mentioned patent.
The residue (XXXI) is prepared starting from the corresponding xe2x80x94CH(CH3)xe2x80x94COOH acid according to U.S. Pat. No. 4,254,274. Equivalent compounds are described in the same patent.
The residue (XXXII) is prepared according to EP 238,226 herein incorporated by reference, when the valence is saturated with xe2x80x94CH2xe2x80x94COOH. Equivalent products are reported in said patents as substituted 1,3,4,9 tetrahydropyrane [3,4-b]indol-1-acetic acids.
The residue (XXXIII) is prepared from pirazolac and the valence is saturated with xe2x80x94CH2xe2x80x94COOH, as mentioned in EP 54,812 herein incorporated by reference. Equivalent products are described in said patent.
The residue (XXXVI) is prepared according to UK 2,035,311 herein incorporated by reference, starting from zaltoprofen and having the xe2x80x94CH(CH3)xe2x80x94COOH end group. Equivalent products are described in said patent.
The preparation process of the residue (XXXVII) is obtained starting from mofezolac and is prepared according to EP 26,928. Equivalents products are reported in the same patent.
The compounds in which R is of the group IV) are described in the British patent application 2,283,238, wherein also the preparation methods are indicated; this patent is herein incorporated by reference.
In the group IV) the compounds can also be obtained: for the compounds of formula (II) using U.S. Pat. No. 3,904,682; the compounds of formula (X) according to U.S. Pat. No. 4,161,538, the compounds of formula (III) according to U.S. Pat. No. 3,228,831. These patents herein mentioned are here incorporated by reference.
In the group V) the compounds can also be obtained: for the compounds of formula (II) using U.S. Pat. No. 4,089,969 herein incorporated by reference; the compounds of formula (V) can be obtained according to U.S. Pat. No. 4,556,672 herein incorporated by reference.
The residue (X) is prepared according to the German patent 2,756,113. Equivalent products are described in said patent.
The residue (XI) is-prepared according to EP 147,177, starting from ampiroxicam having the xe2x80x94CH(CH3)OCOOC2H5 end group. Equivalent products are described in said patent.
The residue (XII) is prepared according to J. Med. Chem., vol. 27 n. 11, November 1984, Walsh et Al. xe2x80x9cAntiinflammatory Agents. 3. Synthesis and Pharmacological Evaluation of 2-amino-3-benzoylphenylacetic Acid and Analoguesxe2x80x9d. Equivalent products are described in said publication.
The residue (XIII) is prepared starting from lornoxicam, wherein the valence is saturated with H. It is prepared according to GE 2,003,877. Equivalent products are described in said patent.
Generally the connection between A and X1 is, as seen, of ester or amidic type (NH or NR1c, as defined in X) when R is of groups I, II, III, IV and V. All well known synthesis routes for forming such bonds may be used to form said connection.
In the case of esters of groups I, II, III and IV, and for the compounds of group V ending with a carboxylic function, the most direct synthetic route to obtain the corresponding nitroxyderivatives of the present invention involves:
a) reaction of the acyl chlorides Rxe2x80x94COxe2x80x94Cl with halogen alcohols of the HOxe2x80x94X1Zxe2x80x94Cl, HOxe2x80x94X1Zxe2x80x94Br, HOxe2x80x94X1Zxe2x80x94I type, wherein X1Z is X1 as above defined without the oxygen atom, in the experimental conditions of the prior art, and isolation of compounds of formula Rxe2x80x94COxe2x80x94Oxe2x80x94X1Zxe2x80x94Cl (Br, I). The above products can also be obtained by reaction of the sodium or potassium salts of said Rxe2x80x94COxe2x80x94OH acids with dihalogen derivatives of general formula X1ZCl2, X1ZBr2 or X1ZI2.
b) The above products are transformed into the final products by reaction with AgNO3 in acetonitrile, according to what known in the prior art.
The general schemes are the following:
Rxe2x80x94COxe2x80x94Cl+HOxe2x80x94X1Zxe2x80x94Brxe2x86x92Rxe2x80x94COxe2x80x94Oxe2x80x94X1Zxe2x80x94Br+AgNO3xe2x86x92Axe2x80x94X1NO2
wherein X1=X1ZO.
Rxe2x80x94COxe2x80x94ONa+Br2X1Zxe2x86x92Rxe2x80x94COxe2x80x94Oxe2x80x94X1Zxe2x80x94Br+AgNO3xe2x86x92Axe2x80x94X1NO2
wherein X1=X1ZO.
In the case of amides the synthetic sequence involves the reaction of the same acyl chlorides RCOCl with aminoalcohols of general formula NH2xe2x80x94X1Zxe2x80x94OH, NHR1Cxe2x80x94X1Zxe2x80x94OH to give amides of general formula:
Rxe2x80x94COxe2x80x94NHxe2x80x94X1Zxe2x80x94OH and Rxe2x80x94COxe2x80x94NR1Cxe2x80x94X1Zxe2x80x94OH
according to known methods.
The reaction of said amides with halogenating agents such as for example PCl5, PBr3, SOCl2 etc. leads to halogen derivatives of general formula:
Rxe2x80x94COxe2x80x94NHxe2x80x94X1Zxe2x80x94Br(Cl) and Rxe2x80x94COxe2x80x94NR1Cxe2x80x94X1Zxe2x80x94Br(Cl).
The latter by reaction with AgNO3 in acetonitrile, according to known methods in the prior art, lead to the final products Axe2x80x94X1xe2x80x94NO2.
The synthesis scheme is the following:

wherein X1ZO is X1.
c) An alternative route to the synthesis through steps a) and b) above is the reaction of the acid sodium or potassium salts with the nitric esters of halogeno-alcohols of general formula:
NO2xe2x80x94Oxe2x80x94X1Zxe2x80x94Cl (Br, I)
xe2x80x83to give directly the nitroxy derivatives of the invention.
The reaction scheme is the following:
Rxe2x80x94COxe2x80x94ONa+Brxe2x80x94X1Zxe2x80x94ONO2xe2x86x92Rxe2x80x94COxe2x80x94Oxe2x80x94X1Zxe2x80x94ONO2
wherein X1ZO is X1.
Synthetic routes similar to those above described are used for the products of group V, for example tenoxicam and piroxicam, wherein a dihalogen derivative of formula Br2X1Z is reacted with the corresponding enolates. The products obtained are then transformed into the compounds of the invention by reaction with AgNO3 in acetonitrile according to the above reported reaction scheme.
The scheme is herein reported for the piroxicam of formula IX of group V. 
Group V products, such as tenoxicam and piroxicam, wherein the antiinflammatory reactive function is an hydroxyl, can be also reacted with an acyl chloride of formula ClCOxe2x80x94X1Zxe2x80x94QI wherein QI is Cl, Br, I, OH. When QI=OH, the hydroxyl is substituted with an halogen as above described before the final nitration reaction with AgNO3.
Nitration is carried out as above described.
In order to obtain the compounds of formula Axe2x80x94X1xe2x80x94NO, acyl chlorides of formula Rxe2x80x94COCl are reacted with HXxe2x80x94X1Zxe2x80x94OH, wherein R, X and X1Z have the above mentioned meanings, in the experimental conditions described in the prior art. The obtained alcohols are reacted with sodium nitrite in a solvent, for instance constituted of a mixture of water with tetrahydrofuran in the presence of hydrochloric acid. The reaction is described in the prior art. The general scheme is the following:
Rxe2x80x94COCl+HXxe2x80x94X1Zxe2x80x94OHxe2x86x92Rxe2x80x94COxe2x80x94Xxe2x80x94X1Zxe2x80x94OH+NaNO2xe2x86x92Axe2x80x94X1xe2x80x94NO
The compounds according to the present invention are transformed into the corresponding salts by reaction in organic solvent such as for example acetonitrile and tetrahydrofuran with an equimolecular amount of the corresponding organic or inorganic acid.
Examples of suitable organic acids are: oxalic, tartaric, maleic, succinic, citric acid.
Examples of suitable inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acid.
Another object of the invention is that it has surprisingly been found that the invention products containing ONxe2x80x94(O)Z groups are able to exert also an inhibiting effect of the inflammation induced by liposaccharide (LPS) and therefore are usable in septic shock.
This is surprising, since it is well known that generally antiinflammatories do not meaningfully change the nitrosynthetase activity induced by lipopolysaccharides in the rat and therefore they cannot be used in septic shock.
The compounds of the present invention can be used as antiinflammatory drugs or for the therapy and prophylaxis of cardiovascular diseases and of those pathologies wherein cellular hyperproliferation plays an important pathogenetic role.
It must be understood that when the compounds of the various groups contain at least one asymmetric carbon, the products can be used in racemic form or as single isomers. It is indeed well known that in the therapeutic uses of the invention generally an isomeric form is more active than the others. When the compounds present cis/transisomers, they can be used in this separated form or in admixture.
The pharmaceutical formulations of the compounds according to the present invention contain the same dose of the antiinflammatory precursor products, or lower.
The pharmaceutical formulations can be given by as or parenterally and can be prepared according to well known processes in the prior art. See the volume xe2x80x9cRemington""s Pharmaceutical Sciencesxe2x80x9d.